Hepatocyte Nuclear Factor 4-Alpha Is Essential for the Active Epigenetic State at Enhancers in Mouse Liver

Avinash Thakur, Jasper C.H. Wong, Evan Y. Wang, Jeremy Lotto, Donghwan Kim, Jung Chien Cheng, Matthew Mingay, Rebecca Cullum, Vaishali Moudgil, Nafeel Ahmed, Shu Huei Tsai, Wei Wei, Colum P. Walsh, Tabea Stephan, Misha Bilenky, Bettina M. Fuglerud, Mohammad M. Karimi, Frank J. Gonzalez, Martin Hirst, Pamela A. Hoodless

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    48 Citations (Scopus)
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    Cell-fate determination is influenced by interactions between master transcription factors (TFs) and cis-regulatory elements. Hepatocyte nuclear factor 4 alpha (HNF4A), a liver-enriched TF, acts as a master controller in specification of hepatic progenitor cells by regulating a network of TFs to control onset of hepatocyte cell fate. Using analysis of genome-wide histone modifications, DNA methylation, and hydroxymethylation in mouse hepatocytes, we show that HNF4A occupies active enhancers in hepatocytes and is essential for active histone and DNA signatures, especially acetylation of lysine 27 of histone 3 (H3K27ac) and 5-hydroxymethylcytosine (5hmC). In mice lacking HNF4A protein in hepatocytes, we observed a decrease in both H3K27ac and hydroxymethylation at regions bound by HNF4A. Mechanistically, HNF4A-associated hydroxymethylation (5hmC) requires its interaction with ten-eleven translocation methylcytosine dioxygenase 3 (TET3), a protein responsible for oxidation from 5mC to 5hmC. Furthermore, HNF4A regulates TET3 expression in liver by directly binding to an enhancer region. Conclusion: In conclusion, we identified that HNF4A is required for the active epigenetic state at enhancers that amplifies transcription of genes in hepatocytes.

    Original languageEnglish
    Pages (from-to)1360-1376
    Number of pages17
    Issue number4
    Early online date1 Apr 2019
    Publication statusPublished (in print/issue) - 8 Oct 2019


    • Histone modification
    • hydroxymethylation
    • hepatoblasts
    • hepatocytes
    • TET3


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